Most lung cancer cells are characterized by elevated levels of anti-apoptotic Bcl-2 family proteins and the resulting inhibition of cell-death influences tumorigenicity, metastatic behavior, chemoresistance and radioresistance. In non-small-cell lung cancer (NSCLC) upregulation of anti-apoptotic Bcl-2 proteins, such as Bcl-xL, Bcl-2 and Mcl-1, is often associated with resistance to traditional chemotherapy and radiation, which are therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might combine traditional chemotherapeutics with molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. Already, Bcl-2- targeting antisense oligonucleotides (GenasenseTM) are in Phase III clinical trials for melanoma and chronic lymphocytic leukemia (CLL), a quintessential example of a human malignancy caused by defective programmed cell death and Bcl-xL/2 over- expression. Similarly, a dual Bcl-xL/Bcl-2 small molecule inhibitor (ABT-263, Abbott) is advancing clinical evaluation for patients affected by CLL. However, several studies suggest that in non-small cell lung cancers (NSCLC), in addition to Bcl-2 and Bcl-xL, Mcl-1 over-expression dictates resistance to chemotherapy and radiation. Hence, we propose to use a highly integrated multidisciplinary approach involving innovative structure-based design, medicinal chemistry, cell-based and in vivo studies to derive novel, potent and drug-like pan-Bcl-2 antagonists that primarily target Mcl-1, Bcl2 and Bcl-xL, focusing on their development against NSCLC. Given the arsenal of techniques and alternative approaches proposed, we anticipate that we will be able to identify novel pan-Bcl-2 antagonists that induce apoptosis in lung cancer cells that are resistant to current advanced compounds such as ABT-263 or Genasense.